Mineralocorticoid receptor antagonists and methods of use

The present invention relates to tricyclic compounds that are useful as therapeutic agents in the treatment of physiological disorders responsive to mineralocorticoid receptor antagonists, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders in patients, and to intermediates and processes useful in the synthesis of the compounds.

Aldosterone, the primary endogenous mineralocorticoid, regulates hemodynamic homeostasis by promoting sodium and water reabsorption and potassium excretion following interaction with the mineralocorticoid receptor (MR). Because of aldosterone\'s role in maintaining electrolyte and water balance, MR antagonists have been used for the treatment of numerous physiological disorders including hypertension, hypokalemia, myocardial arrhythmias, Bartter\'s Syndrome, as well as disorders of primary or secondary hyperaldosteronism such as Conn\'s Syndrome. More recently, MR antagonists have been used in the treatment of congestive heart failure and acute myocardial infarction. In addition, MR antagonists have also proven effective in preclinical models of kidney disease and in combination with standard therapy to reduce proteinuria in patients suffering from renal disorders such as chronic kidney disease including diabetic nephropathy.

However, existing MR antagonists produce concomitant effects which limit their safety and/or effectiveness. For example, spironolactone, a potent MR antagonist, is nonselective and cross reacts with other nuclear hormone receptors (e.g. the androgen receptor (AR), the progesterone receptor (PR), or the glucocorticoid receptor (GR)) which mediate other physiological processes. Spironolactone therapy has been associated with hyperkalemia as well as gynecomastia, erectile dysfunction, reduced libido, irregular menses, as well as gastric distress. Eplerenone, though selective for MR relative to the other nuclear hormone receptors, has also been associated with hyperkalemia. Thus, there remains a need in the art for alternatives to current MR antagonist therapy.

The object of the present invention is to provide nonsteroidal MR ligands which possess MR antagonist activity. As a preferred embodiment, it is an object to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR. As a more preferred embodiment, it is an object of the present invention to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR, and which posses potent reno- or cardio-protective activity. As an even more preferred embodiment, it is an object of the present invention to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR, and which posses potent reno- or cardio-protective activity, but with a reduced incidence or likelihood of producing hyperkalemia.

An important consideration for any therapeutic agent is whether the agent is likely to cause a prolongation of the QT interval. A central mechanism by which therapeutic agents may induce a prolongation of the QT interval is by blocking the hERG channels in cardiac muscle. Blockage of the the hERG channel prevents passage of potassium ions across cardiac cell membranes resulting in prolongation of the action potentials of the cells, which could lead to dangerous cardiac arrhythmias. Thus, a further preferred embodiment of the present invention is to provide MR antagonists with a reduced incidence or likelihood of blocking hERG channels.

Tricyclic MR ligands are known in the art. For example WO 04/052847 and WO 05/066161 disclose tricyclic steroid hormone receptor modulators which are useful for treating disorders susceptible to mineralocorticoid receptor or glucocorticoid receptor modulation. The present invention is directed to the discovery that certain novel tricyclic compounds, as given by Formula (I) below, have particular profiles of activity, as evidenced by in vitro and in vivo testing, which indicate that they have utility in the treatment or prevention of disorders responsive to mineralocorticoid receptor antagonist therapy. In particular, exemplified compounds of Formula (I) are potent MR ligands which antagonize the mineralocorticoid receptor.

Accordingly, the present invention provides a compound of Formula (I)

wherein,

R¹ and R² each independently represent hydrogen or fluoro;

L represents —(CH₂)₂—, —CH(CH₃)—CH₂—, or a direct bond;

R³ represents hydrogen or a group of the formula:

R⁴ represents —CN or —C(O)NH₂, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of treating or preventing congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter\'s Syndrome, primary or secondary hyperaldosteronism, or Conn\'s Syndrome, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. As a more particular aspect, the present invention provides a method for treating or preventing congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease.

Further, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter\'s Syndrome, primary or secondary hyperaldosteronism, or Conn\'s Syndrome. More particularly, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease. In addition, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

In another embodiment, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter\'s Syndrome, primary or secondary hyperaldosteronism, or Conn\'s Syndrome. More particularly, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease.